Introduction

Uses for Aredia

Hypercalcemia Associated with Malignancy

Used in conjunction with achievement and maintenance of adequate hydration for the treatment of moderate to severe hypercalcemia associated with malignant neoplasms, with or without bone metastases.13455253

More conservative measures (e.g., hydration alone or combined with loop diuretics) generally used for treatment of mild or asymptomatic hypercalcemia.15313233395253 Corticosteroid therapy may be beneficial in hypercalcemia associated with hematological malignancies.15253

Consider retreatment in patients with recurrent or refractory disease.15253

Used as an adjunct to antineoplastic therapy for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma.120295253

Decreases the incidence and delays the development of bone-related complications (e.g., fractures or spinal cord compression, bone deterioration requiring radiotherapy or orthopedic surgery), and reduces bone pain and the need for supplemental analgesic therapy.12324275253

Aredia Dosage and Administration

General

Monitor standard laboratory and clinical parameters of renal function (including Scr) prior to each treatment and closely monitor CBC with differential and hematocrit and hemoglobin.15253

Adequately hydrate patients with osteolytic lesions of multiple myeloma and marked Bence-Jones proteinuria who are dehydrated prior to treatment initiation.1395253

In the absence of hypercalcemia, give oral calcium and vitamin D supplementation to minimize the risk of hypocalcemia in patients with predominantly lytic bone metastases or multiple myeloma who are at risk for calcium or vitamin D deficiency.15253

Paget’s Disease of Bone

In the absence of hypercalcemia, give oral calcium and vitamin D supplementation to minimize the risk of hypocalcemia.15253

Rate of Administration

For treatment of hypercalcemia associated with malignancy, infuse over 2–24 hours.15253

For treatment of Paget’s disease of bone, infuse over a 4-hour period once daily for 3 consecutive days.15253

For treatment of osteolytic bone metastases of breast cancer, infuse over a 2-hour period once every 3–4 weeks.15253

For treatment of osteolytic lesions of multiple myeloma, infuse over a 4-hour period once monthly.15253

Dosage

Available as pamidronate disodium; dosage is expressed in terms of the salt.15253

Adults

Hypercalcemia Associated with Malignancy

Moderate Hypercalcemia

IV

60–90 mg as a single dose over 2–24 hours in those with albumin-corrected serum calcium concentration approximately 12–13.5 mg/dL.15253

Consider retreatment if serum calcium concentrations do not return to normal or do not remain normal.15253 In order to allow for full response to the initial dose, repeat the dose appropriate for the degree of hypercalcemia no sooner than 7 days after the initial dose.15253

Severe Hypercalcemia

IV

90 mg as a single dose over 2–24 hours in those with albumin-corrected serum calcium concentration >13.5 mg/dL.15253

Consider retreatment if serum calcium concentrations do not return to normal or remain normal.15253 In order to allow for full response to the initial dose, repeat the dose appropriate for the degree of hypercalcemia no sooner than 7 days after the initial dose.15253

Paget’s Disease of Bone

IV

Initially, 30 mg, administered as a 4-hour infusion, once daily on 3 consecutive days (total cumulative dose 90 mg for the course).15253

Monitor periodically for recurrence of disease (e.g., increased serum alkaline phosphatase concentrations and urinary hydroxyproline); individualize the need for retreatment based on patient response.7891113172540 When clinically indicated, retreat with the same dosage that was required for initial treatment.15253

Osteolytic Bone Metastases of Breast Cancer

IV

Initially, 90 mg, administered as a 2-hour infusion, given once every 3–4 weeks.15253 Optimum duration of such therapy is not known, but has been used for up to at least 24 months in clinical studies.15253

Osteolytic Bone Lesions of Multiple Myeloma

IV

Initially, 90 mg, administered as a 4-hour infusion, given once monthly.15253 Optimum duration of therapy currently is not known, but monthly doses have been administered for up to at least 21 months in clinical studies.15253

Prescribing Limits

Adults

IV

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment; not studied in patients with severe hepatic impairment.15253

Renal Impairment

Withhold therapy in patients with bone metastases associated with solid tumors or with osteolytic lesions associated with multiple myeloma if renal function deteriorates (defined as an increase in Scr of at least 0.5 or 1 mg/dL in patients with normal [<1.4 mg/dL] or elevated [≥1.4 mg/dL] baseline Scr, respectively) during therapy; in clinical trials, pamidronate therapy was not resumed until Scr had returned to within 10% of baseline levels.15253

Geriatric Patients

No specific dosage recommendations; however, select dosage cautiously, usually starting at the lower end of the dosage range, because of possible age-related decreases in hepatic, renal, or cardiac function and concomitant diseases and drug therapy.15253

Cautions for Aredia

Contraindications

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity

May cause fetal harm; use not recommended in pregnant women, and women of childbearing potential should avoid conception during therapy.15253 If patient becomes pregnant, apprise of potential fetal hazard.15253

Renal Effects

Possible renal toxicity (e.g., deterioration of renal function, progression to renal failure and dialysis); may occur after initial or single dose of pamidronate.15253

Focal segmental glomerulosclerosis (including collapsing variant) with or without nephrotic syndrome reported, particularly in patients with multiple myeloma or breast cancer; gradual improvement in some patients following drug discontinuance.15253

Risk of renal toxicity may be greater in patients with impaired renal function.15253

Good oral hygiene and a dental examination (panoramic jaw radiograph) with appropriate preventive dentistry recommended prior to treatment with bisphosphonates in patients with cancer.141424346475253 Avoid invasive dental procedures in such patients if possible during therapy.1424346475253

Severe, occasionally incapacitating bone, joint, and/or muscle pain reported infrequently.1424849515253 Time to onset of symptoms varied from 1 day to years after treatment initiation.14248515253 Such pain generally improves following discontinuance of the drug but has recurred upon subsequent rechallenge in some patients.142484950515253

Hematologic Effects

Anemia, leukopenia, neutropenia, and thrombocytopenia reported.15253 Monitor complete blood counts with differential and hematocrit and hemoglobin.15253 Carefully monitor patients with preexisting anemia, leukopenia, or thrombocytopenia for the first 2 weeks after treatment initiation.15253

Specific Populations

Pregnancy

Lactation

Not known if pamidronate is distributed into milk.15253 Use with caution in nursing women.15253

Pediatric Use

Safety and efficacy not established in children <18 years of age.125253

Geriatric Use

No substantial differences in safety and efficacy relative to younger patients, but increased sensitivity cannot be ruled out.15253 (See Geriatric Use under Dosage and Administration.)

Renal Impairment

Safety and efficacy not established in patients with severe renal impairment (Scr >3 mg/dL).15253 Not recommended for use in patients with severe renal impairment and bone metastases.15253 Carefully weigh possible benefits and risks of therapy in other patients with severe renal impairment.15253 (See Renal Effects under Cautions.)

Specific Drugs

Increased risk of nephrotoxicity with concurrent use in patients with multiple myeloma15253

Aredia Pharmacokinetics

Absorption

Onset

Hypercalcemia associated with malignancy: Reduction of serum calcium concentration usually is apparent within 1–3 days343338 and generally is maximal within 5–7 days.3438

Paget’s disease of bone: Onset of therapeutic response usually is evident within the first week.1175253 Symptomatic relief of bone pain usually is evident within 0.5–3 months after therapy.81340 The median time to appreciable therapeutic response (≥50% decrease from baseline) for serum alkaline phosphatase was approximately 1 month (90-mg dose).15253 Plateau at 5–12 months after therapy.78913172540

Bone metastases of breast cancer: Decrease in bone pain usually is evident within 2 weeks.20

Duration

Hypercalcemia associated with malignancy: Normocalcemia persists for about 6–14 days following a single dose.133033385253

Elimination

Metabolism

Elimination Route

Half-life

Averages 28 hours.15253 Rate of elimination from bone not determined.15253

Special Populations

In cancer patients with renal impairment, decreased clearance compared with cancer patients without renal impairment.15253 Accumulation of pamidronate not anticipated when recommended dose is repeated on a monthly basis;15253 however, limited pharmacokinetic data exist in patients with Clcr <30 mL/minute.15253

In patients with hepatic impairment, decreased plasma clearance.15253 Not thought to be clinically relevant.15253

Hypocalcemic effect appears to result principally from inhibition of bone resorption and does not depend on cytotoxic activity or enhancement of renal calcium excretion.151033385253

Advice to Patients

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.15253 Advise women to avoid pregnancy during therapy.15253 If patient becomes pregnant, apprise of potential fetal hazard.15253

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.15253

Importance of advising patients of other important precautionary information.15253 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

17. Siris ES. Perspectives: a practical guide to the use of pamidronate in the treatment of Paget’s disease. J Bone Miner Res. 1994; 9:303-4. http://www.ncbi.nlm.nih.gov/pubmed/8191921?dopt=AbstractPlus